PROJECT SUMMARY/ABSTRACT Older adults will be disproportionately affected by the complications arising from metabolic diseases including diabetes, heart disease and neurodegeneration, predicted to double between now and 2050. However, the fundamental mechanisms that link obesity and metabolic disease with longevity remain poorly understood. The central nervous system is a major driver of lipid metabolism and lifespan. However neuroendocrine signals that specifically control metabolism and lifespan are poorly understood in any system, and cannot be modeled in cell culture. The long-term goal of my laboratory is to decipher the neural circuits and neuroendocrine mechanisms that regulate metabolism and lifespan, and to define the key regulatory principles that govern their relationship. We have uncovered an integrated neuro-metabolic system that underlies communication between the nervous system and the intestine in the C. elegans model system, in which ancient and conserved aspects of neuroendocrine biology can be discovered with state-of-the-art molecular tools. We define two critical nodes for the regulation of this neuroendocrine system: one neuronal, one metabolic. The neuronal node integrates food and oxygen sensory information from the environment, and the metabolic node integrates fat loss with mitochondrial stress. Our central hypothesis is that the neuronal and metabolic nodes counterbalance one another to maintain the integrity of neuroendocrine homeostasis, and that disruption of this counterbalancing mechanism at either node alters lifespan. The objective of this proposal is to determine the molecular mechanisms that regulate the homeostatic balance between the neuronal and metabolic nodes, and to identify the key drivers that protect longevity. Thus, our neuroendocrine pathway defines a unique and powerful model to study the consequences of neuronally-stimulated lipid metabolism, on longevity. Aim 1 will define the neural circuit mechanisms that integrate neuroendocrine signaling, fat metabolism and lifespan. Our goal is to scale multiple levels of analysis from molecular, circuit-level and organismal properties to achieve mechanistic insights how the activity of a multimodal neural circuit gives rise to coordinated physiological shifts in metabolism and longevity. Aim 2 will identify the mechanistic interactions between neuronally-driven fat loss and mitochondrial stress-sensing pathways in the intestine, which ultimately drive lifespan. Using molecular genetic approaches, biochemical analyses, metabolic and lifespan assays, we will uncover the molecular mechanisms that couple fat loss with stress-protective mechanisms that together determine longevity. A major expected outcome of our proposed studies is that longevity is an emergent property, determined by the extent to which mitochondrial stress in metabolic tissues can counterbalance the neuronal drive for fat loss. The experiments proposed in Aims 1 and 2 are expected to pinpoint, at a molecular level, the integrative mechanisms that underlie this neuroendocrine homeostasis. This knowledge is critical for the future design of safe and effective drugs to combat metabolic diseases that accompany aging.